1. Field of the Invention
The present invention relates to novel proteins having a TNF action, to the preparation thereof, and to the use thereof in therapy.
2. Discussion of the Background
Carswell et al. [Proc. Natl. Acad. Sci. USA 72,3666-3670, 1975] have reported that serum from endotoxin-treated animals which had previously been infected with the Calmette-Guerin (BCG) microbacteria strain brought about hemorrhagic necrosis in various mouse tumors. This activity was attributed to a tumor necrosis factor (TNF). TNF also has a cytostatic or cytotoxic action against a plurality of transformed cell lines in vitro, whereas normal human and animal cell lines are unaffected by this [Ruff and Gifford, Lymphokine Reports Vol. 2, pp 235-275, Academic Press, New York, 1981]. The biochemical characterization and the gene for human TNF have recently been described [Aggarwal et al., J. Biol. Chem. 260 (1985), 2345-2354; Nedwin et al., Nucl. Acids Res. 13 (1985), 6361-6373]. These data allow the following protein structure for mature human TNF to be deduced: ##STR1##
Fibronectin is a glycoprotein which occurs in human plasma and has a molecular weight of about 450,000. It consists of two disulfide-linked polypeptide chains which contain a cell-binding domain [Hynes et al., J. Cell Biol. 95 (1982), 369-377]. The primary structure of this cell-binding domain was established by Pierschbacher et al., J. Biol. Chem. 257 (1982), 9593-9597. The fibronectin molecule is able using this domain to bind to a receptor on the surface of cells such as blood platelets of fibroblasts [Plow and Ginsberg, J. Biol. Chem. 256 (1981) 9477-9482].
Attachment of partial sequences from the cell-binding domain of human fibronectin to the amino terminus of mature human TNF results in hybrid proteins which have more advantageous properties than human TNF itself.